Gene Therapy for Bubble Boy Disease

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Suk S De Ravin, M.D.

Age: < 65

Sex: Male

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Disqualifiers: Hematologic malignancy, HIV, Hepatitis B, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This is a Phase I/II non-randomized clinical trial of ex vivo hematopoietic stem cell (HSC) gene transfer treatment for X-linked severe combined immunodeficiency (XSCID, also known as SCID-X1) using a self-inactivating lentiviral vector incorporating additional features to improve safety and performance. The study will treat 35 patients with XSCID who are between 2 and 50 years of age and who have clinically significant impairment of immunity. Patients will receive a total busulfan dose of approximately 6 mg/kg/body weight (target busulfan Area Under Curve is 4500 min\*micromol/L/day) delivered as 3mg/kg body weight on day 1 and dose adjusted on day 2 (if busulfan AUC result is available) to achieve the target dose, to condition their bone marrow, and this will be followed by a single infusion of autologous transduced CD34+HSC. Patients will then be followed to evaluate engraftment, expansion, and function of gene corrected lymphocytes that arise from the transplant; to evaluate improvement in laboratory measures of immune function; to evaluate any clinical benefit that accrues from the treatment; and to evaluate the safety of this treatment. The primary endpoint of the study with respect to these outcomes will be at 2 years, though data relevant to these measures will be collected at intervals throughout the study and during the longer follow-up period of at least 15 years recommended by the Food and Drug Administration (FDA) Guidance "Long Term Follow-Up After Administration of Human Gene Therapy Products" https://www.fda.gov/media/113768/download for patients participating in gene transfer clinical trials. XSCID results from defects in the IL2RGgene encoding the common gamma chain (yc) shared by receptors for Interleukin 2 (IL-2), IL-4, IL-7, IL-9, IL-15 and IL-21. At birth XSCID patients generally lack or have a severe deficiency of T-lymphocytes and NK cells, while their B- lymphocytes are normal in number but are severely deficient in function, failing to make essential antibodies. The severe deficiency form of XSCID is fatal in infancy without intervention to restore some level of immune function. The best current therapy is a T-lymphocyte-depleted bone marrow transplant from an HLA tissue typing matched sibling, and with this type of donor it is not required to administer chemotherapy or radiation conditioning of the patient's marrow to achieve excellent engraftment and immune correction of an XSCID patient. However, the great majority of patients with XSCID lack a matched sibling donor, and in these patients the standard of care is to perform a transplant of T- lymphocyte depleted bone marrow from a parent. This type of transplant is called haploidentical because in general a parent will be only half- matched by HLA tissue typing to the affected child. Whether or not any conditioning is used, haploidentical transplant for XSCID has a significantly poorer prognosis than a matched sibling donor transplant. Following haploidentical transplant, XSCID patients are observed to achieve a wide range of partial immune reconstitution and that reconstitution can wane over time in some patients. That subset of XSCID patients who either fail to engraft, fail to achieve adequate immune reconstitution, or lose immune function over time suffer from recurrent viral, bacterial and fungal infections, problems with allo- or autoimmunity, impaired pulmonary function and/or significant growth failure. We propose to offer gene transfer treatment to XSCID patients\^3 \>= 2 years of age who have clinically significant defects of immunity despite prior haploidentical hematopoietic stem cell transplant, and who lack an HLA-matched sibling donor. Our current gene transfer treatment protocol can be regarded as a salvage/rescue protocol. Prior successful retroviral gene transfer treatment instead of bone marrow transplant (BMT) in Paris and London for 20 infants with XSCID has provided proof of principle for efficacy. However, a major safety concern is the occurrence of 5 cases of leukemia at 3-5 years after treatment triggered in part by vector insertional mutagenesis activation of LMO2 and other DNA regulatory genes by the strong enhancer present in the long-terminal repeat (LTR) of the Moloney Leukemia Virus (MLV)- based vector. Furthermore, previous studies of gene transfer treatment of older XSCID patients with MLV- based vectors demonstrated the additional problem of failure of adequate expansion of gene corrected T- lymphocytes to the very high levels seen in infants. To reduce or eliminate this leukemia risk, and possibly enhance performance sufficiently to achieve benefit in older XSCID patients, we have generated a lentivector with improved safety and performance features. We have generated a self-inactivating (SIN) lentiviral vector that is devoid of all viral transcription elements; that contains a short form of the human elongation factor 1a (EF1a) internal promoter to expres......

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, since the trial involves gene therapy and conditioning with busulfan, it's important to discuss your current medications with the trial team to ensure there are no interactions.

What data supports the effectiveness of the treatment Lentiviral Gene Transfer for Bubble Boy Disease?

Gene therapy has shown positive outcomes in treating various genetic diseases, including primary immunodeficiencies like SCID (Severe Combined Immunodeficiency), by restoring the immune system in children. Lentiviral vectors, which are used in this treatment, have been improved to safely and effectively deliver therapeutic genes, offering hope for lasting correction of immune deficiencies. ^{1 2 3 4 5}

How is Lentiviral Gene Transfer treatment different from other treatments for Bubble Boy Disease?

Lentiviral Gene Transfer is unique because it uses a virus to deliver a healthy gene into the patient's cells, which can integrate into both dividing and non-dividing cells, providing a long-term solution. This is different from other treatments that may not offer permanent genetic correction or may not work effectively in non-dividing cells. ^{4 6 7 8 9}

Research Team

Suk S De Ravin, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

This trial is for children and adults aged 2 to 40 with X-linked severe combined immunodeficiency (XSCID) who lack a matched sibling bone marrow donor, may have had an unsuccessful half-matched transplant, and show significant immune impairment. Participants must weigh at least 10 kg, be HIV negative, have documented B cell dysfunction or need for IVIG therapy, and be able to comply with the study's long-term follow-up.

Inclusion Criteria

Your doctor needs to believe that you have a supportive family and social situation that will help you follow the study's plan and long-term check-ups.

My DNA test shows a mutation in the common gamma chain gene.

I am between 2 and 40 years old and weigh at least 10 kg.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Patients receive a total busulfan dose to condition their bone marrow, followed by an infusion of autologous transduced CD34+HSC

1 week

Daily visits for busulfan administration and monitoring

Gene Transfer Treatment

Patients receive a single infusion of the transduced cells and are monitored for safety and efficacy

1 week

Inpatient stay for infusion and initial monitoring

Follow-up

Participants are monitored for engraftment, expansion, and function of gene-corrected lymphocytes, as well as safety and clinical benefit

2 years

Frequent visits for laboratory and clinical evaluations

Long-term Follow-up

Long-term safety and efficacy evaluation as recommended by FDA Guidance for gene transfer treatment studies

At least 15 years

Treatment Details

Interventions

• Lentiviral Gene Transfer (Virus Therapy)

Trial Overview The trial tests gene transfer using lentiviral vectors in patients' own blood stem cells to treat XSCID. The process involves collecting these cells from the patient, treating them with a corrective gene vector in culture, then returning them via vein after pre-treatment with low-dose busulfan chemotherapy and palifermin to reduce mucositis side effects.

Participant Groups

Group I: cohort b Experimental Treatment 3 Interventions

Patients 9 and Beyond

Group II: cohort a Experimental Treatment 3 Interventions

First 8 Patients Treated

Lentiviral Gene Transfer is already approved in United States for the following indications:

🇺🇸 Approved in United States as Lentiviral Gene Transfer for:

• X-linked severe combined immunodeficiency (XSCID)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, MD

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3361

Patients Recruited

5,516,000+

References

1. United States pubmed.ncbi.nlm.nih.gov

Clinical development of gene therapy: results and lessons from recent successes. [2022] Therapeutic gene transfer holds the promise of providing lasting therapies and even cures for diseases that were previously untreatable or for which only temporary or suboptimal treatments were available. For some time, clinical gene therapy was characterized by some impressive but rare examples of successes and also several setbacks. However, effective and long-lasting treatments are now being reported from gene therapy trials at an increasing pace. Positive outcomes have been documented for a wide range of genetic diseases (including hematological, immunological, ocular, and neurodegenerative and metabolic disorders) and several types of cancer. Examples include restoration of vision in blind patients, eradication of blood cancers for which all other treatments had failed, correction of hemoglobinopathies and coagulation factor deficiencies, and restoration of the immune system in children born with primary immune deficiency. To date, about 2,000 clinical trials for various diseases have occurred or are in progress, and many more are in the pipeline. Multiple clinical studies reported successful treatments of pediatric patients. Design of gene therapy vectors and their clinical development are advancing rapidly. This article reviews some of the major successes in clinical gene therapy of recent years.

2. Switzerland pubmed.ncbi.nlm.nih.gov

Gene therapy for primary immunodeficiency disease. [2012] Gene therapy offers the potential for developing innovative new treatments for both inherited monogenic diseases as well as polygenic and acquired disorders. For most potential clinical applications, the technology has not yet progressed to the stage where it might be reasonably tested. Problems to be solved include the isolation and characterization of the genes involved, the development of gene delivery systems that will permit efficient gene insertion in the affected cells and tissues, and the development of mechanisms to control or appropriately regulate expression of the introduced genes. The primary immunodeficiency diseases as a group actually lend themselves to the development of gene therapy strategies with current technology more readily than almost any other class of disease. Theoretically any genetic disease that can be successfully treated by allogeneic bone marrow transplantation is a potential candidate for gene therapy directed at correcting the patient's own totipotent bone marrow stem cells. In addition, some disorders lend themselves to genetic correction of more mature cells, although gene transfer in this treatment strategy might have to be repeated periodically. The rationale and preliminary results of the first gene therapy protocol for ADA deficiency SCID are described and strategies for developing somatic cell gene therapy for the other primary immunodeficiency diseases are discussed.

3. United States pubmed.ncbi.nlm.nih.gov

Gene therapy for primary adaptive immune deficiencies. [2013] Gene therapy has become an option for the treatment of 2 forms of severe combined immunodeficiency (SCID): X-linked SCID and adenosine deaminase deficiency. The results of clinical trials initiated more than 10 years ago testify to sustained and reproducible correction of the underlying T-cell immunodeficiency. Successful treatment is based on the selective advantage conferred on T-cell precursors through their expression of the therapeutic transgene. However, "first-generation" retroviral vectors also caused leukemia in some patients with X-linked SCID because of the constructs' tendency to insert into active genes (eg, proto-oncogenes) in progenitor cells and transactivate an oncogene through a viral element in the long terminal repeat. These elements have been deleted from the vectors now in use. Together with the use of lentiviral vectors (which are more potent for transducing stem cells), these advances should provide a basis for the safe and effective extension of gene therapy's indications in the field of primary immunodeficiencies. Nevertheless, this extension will have to be proved by examining the results of the ongoing clinical trials.

4. United States pubmed.ncbi.nlm.nih.gov

Progress in gene therapy for primary immunodeficiencies using lentiviral vectors. [2022] This review gives an overview over the most recent progress in the field of lentiviral gene therapy for primary immunodeficiencies (PIDs). The history and state-of-the-art of lentiviral vector development are summarized and the recent advancements for a number of selected diseases are reviewed in detail. Past retroviral vector trials for these diseases, the most recent improvements of lentiviral vector platforms and their application in preclinical development as well as ongoing clinical trials are discussed.

5. United States pubmed.ncbi.nlm.nih.gov

Gene therapy for neurologic disease: benchtop discoveries to bedside applications. 2. The bedside. [2017] Important advances in basic research have made it possible to examine the safety, toxicity, and efficacy of gene therapy in humans for over 5 years. The development of sophisticated gene delivery systems has resulted in approval by the Recombinant DNA Advisory Committee (RAC) of 125 gene therapy or gene marking studies. One of the primary applications of current retroviral-mediated gene insertion technology has been for malignant brain tumors. Studies are therefore underway to examine the efficacy of "suicide" gene therapy in children with recurrent brain tumors and adults with newly diagnosed or recurrent gliomas. Since a high proportion of genetic disorders produce neurologic dysfunction, gene therapy is likely to impact the management of neurologic disease in the foreseeable future. Patients with human immunodeficiency virus (HIV), Gaucher's disease, and Hunter syndrome are now enrolled in gene therapy trials. It will be challenging for the child neurologist to stay abreast of rapid developments in the field of gene therapy. By participating in the design and implementation of clinical trials in gene therapy, the neurologist may reduce the intense toll that several neurologic diseases take on children and their families.

6. United States pubmed.ncbi.nlm.nih.gov

Vectors derived from the human immunodeficiency virus, HIV-1. [2019] The aim of gene therapy is to modify the genetic material of living cells to achieve therapeutic benefit. Gene therapy involves the insertion of a functional gene into a cell, to replace an absent or defective gene, or to fight an infectious agent or a tumor. At present, a variety of somatic tissues are being explored for the introduction of foreign genes with a view towards treatment. A prime requirement for successful gene therapy is the sustained expression of the therapeutic gene without any adverse effect on the recipient. A highly desirable vector should be generated at high titers, stably integrate into target cells (including non-dividing cells), be nonpathogenic, and have little or no associated immune reaction. Lentiviruses have the ability to infect and stably integrate their genes into the genome of dividing and non-dividing cells and, therefore, constitute ideal candidates for development of vectors for gene therapy. This review presents a description of available lentivirus vectors, including vector design, applications to disease treatment and safety considerations. In addition, general aspects of the biology of lentiviruses with relevance to vector development will be discussed.

7. United States pubmed.ncbi.nlm.nih.gov

Lentiviral vectors and gene therapy. [2019] Gene therapy is a novel method under investigation for the treatment of genetic, metabolic and neurologic diseases, cancer and AIDS. The primary goal of gene therapy is to deliver a specific gene to a pre-determined target cell, and to direct expression of such a gene in a manner which will result in a therapeutic effect. Retroviral vectors have the ability to integrate in the host cell DNA irreversibly and therefore, are suitable vectors for permanent genetic modification of cells. Retrovirus-mediated gene transfer has been limited, however, by the inability of onco-retroviruses to productively infect non-dividing cells. Lentiviruses are unique among retroviruses because of their ability to infect target cells independently of their proliferation status. This chapter presents an up-to-date description of available lentiviral vectors, including vector design, applications to disease treatment and safety considerations. In addition, general aspects of the biology of lentiviruses with relevance to vector development will be discussed.

8. England pubmed.ncbi.nlm.nih.gov

Retroviral vectors for gene therapy. [2012] Since their first clinical trial 20 years ago, retroviral (gretroviral and lentiviral) vectors have now been used in more than 350 gene-therapy studies. Retroviral vectors are particularly suited for gene-correction of cells due to long-term and stable expression of the transferred transgene(s), and also because little effort is required for their cloning and production. Several monogenic inherited diseases, mostly immunodeficiencies, can now be successfully treated. The occurrence of insertional mutagenesis in some studies allowed extensive analysis of integration profiles of retroviral vectors, as well as the design of lentiviral vectors with increased safety properties. These new-generation vectors will enable us to continue the successful story of gene therapy, and treat more patients and even more complex diseases.

9. England pubmed.ncbi.nlm.nih.gov

Lentivirus and foamy virus vectors: novel gene therapy tools. [2019] The aim of gene therapy is to modify the genetic material of living cells to achieve therapeutic benefit. Gene therapy involves the insertion of a functional gene into a cell, to replace an absent or defective gene, or to fight an infectious agent or a tumour. At present, a wide variety of somatic tissues are being explored for the introduction of foreign genes with a view towards treatment. A prime requirement for successful gene therapy is the sustained expression of the therapeutic gene without any adverse effect on the recipient. A highly desirable vector would be generated at high titres, integrate into target cells (including non-dividing cells) and have little or no associated immune reactions. Lentiviruses have the ability to infect dividing and non-dividing cells and, therefore, constitute ideal candidates for development of vectors for gene therapy. This review presents a description of available lentiviral vectors, including vector design, applications to disease treatment and safety considerations. In addition, general aspects of the biology of lentiviruses with relevance to vector development will be discussed. Recent investigations have revealed that foamy viruses, another group of retroviruses, are also capable of infecting non-dividing cells. Thus, foamy virus vectors are actively being developed in parallel to lentivirus vectors. This review will also include various aspects of the biology of foamy viruses with relevance to vector development.